Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Reexamination Certificate
1997-11-19
2001-12-25
Guzo, David (Department: 1636)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
C424S093100, C424S093600, C435S320100, C435S455000, C435S456000, C435S457000
Reexamination Certificate
active
06333030
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of molecular biology of vectors and gene therapy. More specifically, the present invention relates to a chimeric adenoviral vector system and methods for its use.
2. Description of the Related Art
A number of gene therapy strategies for diseases of the heart, lung, and blood are based upon stable genetic modification of relevant parenchymal cells. In many contexts, this can be only achieved by direct in vivo gene delivery whereby stable transduction is achieved in situ. To this end, a variety of viral vectors have been developed to exploit their integrative capacity as a means to achieve stable genetic transduction. Vectors of this type include recombinant retroviruses and adeno-associated viruses (AAV) and have been employed in ex vivo gene transfer schemes to achieve stable genetic modification of target cells.
Despite the utility of retroviral and AAV vectors in these ex vivo contexts, employment of these vectors for direct in vivo gene delivery has been problematic. In this regard, issues of effective titer and in vivo stability have limited the utility of these vectors for the many schemes whereby direct in situ transduction of a parenchyma is required. On the other hand, recombinant adenoviral vectors can be prepared to high titer, and possess in vivo stability, both factors which have allowed their employment for direct in vivo gene delivery to differentiated target cells. The limitation of adenoviral vectors, however, is that the derived heterologous gene expression is only transient. This is based, in part, upon the fact that adenoviral vector transduced cells are immunologically eradicated by the host. In addition, the parent adenovirus lacks the capacity to integrate its genome in the host chromosome.
The prior art is deficient in the lack of effective vector system which allows stable genetic modification of cells after direct in vivo vector administration. The present invention fulfills this longstanding need and desire in the art.
SUMMARY OF THE INVENTION
Retroviral integrative functions can be exploited, in the context of adenoviral vectors, to derive a system which can achieve efficient, stable transduction of target cells in vivo. The present invention shows that retroviral vector packaging and retroviral vector functions can operate in the context of adenoviral vector constructs, with the successful derivation of integrative progeny retroviral vectors. In this schema, target cells are induced to function as transient retroviral “producer cells” by a combination of adenoviral vector-mediated delivery of retroviral vector sequences in concert with adenoviral vector expression of retroviral packaging function. In the in vivo context, high efficiency delivery of retroviral packaging and vector functions could be achieved at parenchymal sites via adenoviral vectors to achieve this in situ.
Thus, locally elaborated retroviral vectors could secondarily infect neighbor cells to achieve stable genetic transduction. Thus, a “chimeric” vector system has been developed which exploits favorable characteristics of each component vector.
It is an object of the present invention to develop adenoviral vectors containing retroviral integrative functions and to optimize their employment in vitro, for achievement of stable transduction of target cells.
It is another object of the present invention to employ these chimeric vectors to achieve stable in vivo genetic modification of parenchymal cells relevant to diseases of the heart, lung, and blood.
The development of adenoviral vectors with integrative capacity would allow these vectors to achieve stable integration of transgenes in vivo. This strategy would thus exploit the favorable characteristics of each component vector system to allow stable gene expresssion at parenchymal target sites significantly improving the possibilities of achieving effective genetic correction in the context of gene therapy applications for diseases of the heart, lung, and blood.
In one embodiment of the present invention, there is provided a chimeric adenoviral/retroviral vector, comprising: at least one adenoviral vector containing retroviral sequences.
In one embodiment of the present invention, there is provided method of stably transducing target cells, comprising the step of administering the chimeric adenoviral/retroviral vector of the present invention to an individual in need of such treatment.
Other and further aspects, features, and advantages of the present invention will be apparent from the following description of the presently preferred embodiments of the invention given for the purpose of disclosure.
REFERENCES:
Berkner, K. L., Current Topics in Microbiology and Immunology, vol. 158, pp. 39-66.*
Kmiec, American Scientist, vol. 87, pp. 240-147, May 1999.*
Fox, Nature Biotechnology, vol. 18, pp. 143-144, Feb. 2000.*
Verma et al., Nature, vol. 389, pp. 239-242, Sep. 1997.*
Anderson, Nature, vol. 392, pp. 25-30, Apr. 1998.*
Ross et al., Human Gene Therapy, vol. 7, pp. 1781-1790, Sep. 1996.*
Reynolds et al., Molecular Medicine Today, pp. 25-31, Jan. 1999.
Adler Benjamin Aaron
Guzo David
UAB Research Foundation
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